Cigarette smoking is the single most important preventable cause of morbidity, mortality, and excess health care costs in the United States. Substance abuse causes our nation $137 billion annually in preventable health care costs, with tobacco ($96 billion) contributing to the overwhelming majority of this expense. The World Health Organization declared tobacco-related disease a global epidemic, predicted to cause an estimated 8 million annual deaths worldwide by 2030, if unabated. Advancements in the treatment of patients for tobacco dependence have been made with the introduction of pharmacotherapeutics, varenicline and bupropion. Despite proven efficacy in enabling patients to achieve abstinence, most patients do not achieve long-term tobacco abstinence with these currently recommended monotherapies. In addition, significant variation exists in how individuals respond to the drug therapies. Given this, there exists a significant need for additional pharmacotherapeutics that can be added to a physician's armamentarium for use in the treatment of tobacco dependence. Our preclinical zebrafish model for acute nicotine response in the presence of varenicline or bupropion treatment provides a novel platform for studying existing medications that may mediate nicotine response and be repurposed for the treatment of tobacco dependence. To accomplish this, we will use two complementary zebrafish assays in the following Specific Aims: AIM 1: Identify medications that attenuate nicotine-induced locomotor activation in larval zebrafish. Our working hypothesis is a subset of the existing medications when tested will attenuate the locomotor activating properties of nicotine without causing general malaise or loss of locomotor activity induced by non-nicotine stimuli. We will systematically evaluate 660 physician-vetted, FDA approved medications using the larval zebrafish assay. AIM 2: Identify medications that inhibit nicotine-induced conditioned place preference in adult zebrafish. Our working hypothesis is a subset of existing medications will interfere with the rewarding properties of nicotine and thereby inhibit nicotine-induced conditioned place preference (CPP). We will systematically evaluate 40 medications using the adult zebrafish CPP assay. Medications attenuating nicotine-induced larval locomotion will be prioritized.